The overall goal of this project is to provide a better understanding of the neuronal basis of human memory in health and disease. Loss of the ability to transform present experience to what can be later remembered is one of the most dreaded afflictions of the human condition. It is one of the first features of Alzheimer's Disease (AD) which affects millions of people in the US and worldwide, and is an unwelcome companion of the aging process becoming an increased burden on individual and society. Decades of research have established that declarative memory, the ability to remember recently experienced facts and events, depends on the hippocampus and associated structures in the medial temporal lobe (MTL), including entorhinal, perirhinal and parahippocampal cortices. However, the specific role of each of these sub-structures still remains unclear and continues to be an active area of research. In particular, the role of the hippocampus and its relationship to afferent input from the entorhinal cortex is of considerable significance, as insult to this connective circuitry is very early and disproportionally affected in AD, temporal lobe epilepsy and other neurological disorders, resulting in profound effects on memory. The present project targets specific questions of hippocampal and entorhinal cortex physiology from single neuron activity to local fields to ultimate electrical stimulation of critical nodes in this system in ordr to enhance human memory. The project utilizes a rare opportunity to record the activity of single neurons from depth electrodes implanted in patients with intractable epilepsy in order to identify the seizure focus for potential surgical cure. To this date NIH-funded studies in the applicant's laboratory elucidated key characteristics of single neuron and local field responses to complex visual stimuli and locations during episodic memory and spatial navigation tasks. To complement the previous discovery of place cells in the human hippocampus, the project moves to seek direct evidence for grid cells in humans. This will hopefully not only bring in line one of the major discoveries in rodent physiology with the human MTL system, but will also extend it to particular aspects of human memory. Building on the previous findings of pattern completion and invariance of representation in the human MTL the project will investigate pattern separation in human hippocampal subfields CA3 and dentate gyrus. A primary objective is to characterize the complex phase-relationship between single neuronal responses and local field potentials during these memory tasks. Finally, the project will examine the possibility for spatial and non-spatial memory enhancement by electrical stimulation of the major inputs into the subfields of the human hippocampus. By these three lines of investigation the project aims to develop a detailed understanding of the functional physiology of human MTL, to relate it to key findings in rodent physiology and to contribute to novel therapeutic approaches to human memory disorders. !